Bottom Line:
Biochemical analyses showed that TRIM30α interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response.Overexpression of TRIM30α promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway.These findings indicate that E3 ligase TRIM30α is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING.

Affiliation: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Sciences, University of Science and Technology of China, Hefei, China.

ABSTRACTUncontrolled immune responses to intracellular DNA have been shown to induce autoimmune diseases. Homeostasis regulation of immune responses to cytosolic DNA is critical for limiting the risk of autoimmunity and survival of the host. Here, we report that the E3 ubiquitin ligase tripartite motif protein 30α (TRIM30α) was induced by herpes simplex virus type 1 (HSV-1) infection in dendritic cells (DCs). Knockdown or genetic ablation of TRIM30α augmented the type I IFNs and interleukin-6 response to intracellular DNA and DNA viruses. Trim30α-deficient mice were more resistant to infection by DNA viruses. Biochemical analyses showed that TRIM30α interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response. Overexpression of TRIM30α promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway. These findings indicate that E3 ligase TRIM30α is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING.

Mentions:
To evaluate the function of TRIM30α in host antiviral responses in vitro, we knocked down the expression of TRIM30α in mouse fibroblast L929 cells and then infected these cells with the DNA virus HSV-1. As expected, TRIM30α knockdown suppressed HSV-1 infection (Fig 3A). In contrast, overexpression of TRIM30α markedly facilitated HSV-1 replication (Fig 3B). These data suggest that TRIM30α is an important negative regulator in anti-viral defense. To further identify the role of TRIM30α in vivo host defense, wild type and Trim30α-deficient mice were challenged by intraperitoneal (i.p.) injection with HSV-1, and virus titers were examined 20 h later. Significantly more HSV-1 replication was detected in wild type mice (Fig 3C).

Mentions:
To evaluate the function of TRIM30α in host antiviral responses in vitro, we knocked down the expression of TRIM30α in mouse fibroblast L929 cells and then infected these cells with the DNA virus HSV-1. As expected, TRIM30α knockdown suppressed HSV-1 infection (Fig 3A). In contrast, overexpression of TRIM30α markedly facilitated HSV-1 replication (Fig 3B). These data suggest that TRIM30α is an important negative regulator in anti-viral defense. To further identify the role of TRIM30α in vivo host defense, wild type and Trim30α-deficient mice were challenged by intraperitoneal (i.p.) injection with HSV-1, and virus titers were examined 20 h later. Significantly more HSV-1 replication was detected in wild type mice (Fig 3C).

Bottom Line:
Biochemical analyses showed that TRIM30α interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response.Overexpression of TRIM30α promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway.These findings indicate that E3 ligase TRIM30α is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING.

Affiliation:
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Sciences, University of Science and Technology of China, Hefei, China.

ABSTRACTUncontrolled immune responses to intracellular DNA have been shown to induce autoimmune diseases. Homeostasis regulation of immune responses to cytosolic DNA is critical for limiting the risk of autoimmunity and survival of the host. Here, we report that the E3 ubiquitin ligase tripartite motif protein 30α (TRIM30α) was induced by herpes simplex virus type 1 (HSV-1) infection in dendritic cells (DCs). Knockdown or genetic ablation of TRIM30α augmented the type I IFNs and interleukin-6 response to intracellular DNA and DNA viruses. Trim30α-deficient mice were more resistant to infection by DNA viruses. Biochemical analyses showed that TRIM30α interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response. Overexpression of TRIM30α promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway. These findings indicate that E3 ligase TRIM30α is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING.